The Tau protein is a major Microtubule Associated Protein (MAP) widely expressed in the central nervous system, predominantly in neurons, where it plays a key role in regulating microtubule dynamics, axonal transport and neurite outgrowth. Protein Tau occurs in the adult human brain under six different isoforms generated by alternative splicing of exons 2, 3 and 10 of a primary transcript of a unique gene located on chromosome 17. The length of their sequences varies from 352 to 441 amino acids. Growing evidence suggests that aberrant assembly of “aggregated” Tau (natively unfolded protein) is a hallmark of a series of human cognitive diseases collectively referred to as tauopathies or neurological disorders involving Tau dysfunction, which include Alzheimer's disease, Pick's disease, corticobasal degeneration, mild cognitive impairment, progressive supranuclear palsy, and frontotemporal dementia with chromosome 17-linked parkinsonism. Abnormalities of Tau such as hyperphosphorylation, mutation, truncation and the aggregation in “tangles” may be contributing factors to the pathogenic processes. To date the role of Tau modifications in the induction of neurodegenerative diseases is not fully understood and deciphering the molecular mechanism(s) which control(s) Tau structure/function is therefore of great interest and may help to find novel therapeutic approaches for these diseases.
The instant invention is based on the discovery that Tau protein (all 6 isoforms) binds specifically and directly the immunophilin FKBP52 (FK506-Binding Protein). FKBPs are a family of ubiquitously expressed intracellular receptors for the powerful immunosuppressant drugs FK506 and Rapamycin and therefore take place in the large group of proteins known as immunophilins. These proteins show a large distribution and are particularly abundant in the nervous system suggesting novel and unexpected functions distinct from their immunomodulatory effects. In addition, neuroprotective effects of FK506 have been reported. These latter observations have provided new perspectives for the FKBP protein family and a particular interest for FK506 and its non immunosuppressive derivative molecules as factors to devise new therapeutic assay for treating lesions and diseases of the nervous system.
FKBP52, first identified and cloned as associated to steroid receptor (Lebeau et al., 1992), presents a modular organization. Including four individual and functional domains (Callebaut et al., 1992). The FK506 binding site of FKBP52 (domain I) localized in the N-terminal part of the protein (aa 1 to 149) contains a peptidyl prolyl-isomerase (PPIase) activity (Chambraud et al., 1993) characteristic of all immunophilin protein family. While the second domain (aa 149 to 267) shares structural homology with domain I, the PPIase activity is residual and it does not bind FK506 (14,15); a noteworthy aspect of domain II is a consensus ATP-GTP-binding sequence (16). The C-terminal domain, covering domains III and IV, includes a putative calmodulin binding site (Massol et al., 1992) and mediates, through its three tetratricopeptide repeat (TPR) (aa 273 to 389) the protein's interaction with HSP90 (Radanyi et al., 1994) which is also a component of steroid receptor complex (Catelli et al., 1980, Tai et al., 1986; Renoir et al., 1990). In addition the binding activity of FKBP52 with HSP90 is regulated by casein kinase II which specifically phosphorylates FKBP52 (Myata et al., 1997).
Recently it has been reported that FKBP52 interacts with microtubules and prevents tubulin polymerization (Chambraud et al., 2007). Results obtained so far suggest that this inhibition of tubulin polymerization by FKBP52 may not only result from the sequestration of tubulin or from a modification of its structure, such a bending, by FKBP52, but that another important factor required in the assembling of tubulin into microtubules may be involved.
The inventors now postulate herein that the intervention of one or more microtubule stabilizing factor(s), such as microtubule-associated proteins (MAPs), could explain the inhibition of tubulin polymerization by FKBP52. Using classical biochemical and cellular approaches they establish solid foundations to the role of FKBP52 on Tau function and discover a direct and specific interaction between FKBP52 and Tau. This FKBP52-Tau interaction results in the modulation of the known Tau-mediated cellular functions such as: tubulin polymerization (FKBP52 inhibits this function), Tau accumulation (FKBP52 inhibits this accumulation) and neurite outgrowth.